Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial KATP channels during reperfusion

• Published in: Basic research in cardiology 2008-09, Vol.103 (5), p.472-484
• Main Authors: Mykytenko, James, Reeves, James G., Kin, Hajime, Wang, Ning-Ping, Zatta, Amanda J., Jiang, Rong, Guyton, Robert A., Vinten-Johansen, Jakob, Zhao, Zhi-Qing
• Format: Article
• Language: English
• Subjects: Cardiology; Medicine; Medicine & Public Health; Original Contribution
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-008-0731-2

This study tested the hypothesis that inhibition of myocardial injury and modulation of mitochondrial dysfunction by postconditioning (Postcon) after 24 h of reperfusion is associated with activation of K ATP channels. Thirty dogs undergoing 60 min of ischemia and 24 h of reperfusion (R) were randomly divided into four groups: Control: no intervention at R; Postcon: three cycles of 30 s R alternating with 30 s re-occlusion were applied at R; 5-hydroxydecanoate (5-HD): the mitochondrial K ATP channel blocker was infused 5 min before Postcon; HMR1098: the sarcolemmal K ATP channel blocker was administered 5 min before Postcon. After 24 h of R, infarct size was smaller in Postcon relative to Control (27 ± 4%* Vs. 39 ± 2% of area at risk), consistent with a reduction in CK activity (66 ± 7* Vs. 105 ± 7 IU/g). The infarct-sparing effect of Postcon was blocked by 5-HD (48 ± 5% † ), but was not altered by HMR1098 (29 ± 3%*), consistent with the change in CK activity (102 ± 8 † in 5-HD and 71 ± 6* IU/g in HMR1098). In H9c2 cells exposed to 8 h hypoxia and 3 h of reoxygenation, Postcon up-regulated expression of mito-K ATP channel Kir6.1 protein, maintained mitochondrial membrane potential and inhibited mitochondrial permeability transition pore (mPTP) opening evidenced by preserved fluorescent TMRE and calcein staining. The protective effects were blocked by 5-HD, but not by HMR1098. These data suggest that in a clinically relevant model of ischemia-reperfusion (1) Postcon reduces infarct size and decreases CK activity after prolonged reperfusion; (2) protection by Postcon is achieved by opening mitochondrial K ATP channels and inhibiting mPTP opening. * P